There is increasing evidence to suggest that gamma-delta T cells play an important role in defense against a variety of malignancies in humans. Human gamma-delta T cells expand in vivo, and can become up to 42% of all peripheral blood T cells during non-Hodgkin's lymphoma. This gamma-delta T cell expansion can be recapitulated in vitro by culturing peripheral blood mononuclear cells (PBMC) with lymphoma or myeloma cell lines, and the expanded gamma-delta T cells from such cultures can kill a wide variety of lymphoid myeloid, and epithelial tumor cells. Reconstitution of severe combined immunodeficiency (SCID) mice with human gamma/delta T cells prolongs survival from lymphoma. However, the basis of tumor cell recognition by human gamma-delta T cells is poorly understood, and very little data exists regarding the in vivo regulation of human gamma-delta T cells. This lack of knowledge of human gamma-delta T cell cancer biology is critically important, since information from mouse gamma-deltaT cell studies cannot be readily extrapolated to humans, since non-peptide alkylamine and organophosphate antigens recognized by the dominant population of human peripheral blood gamma-delta T cells, Vgamma2Vdelta T cells, are completely different from the protein antigens recognized by mouse gamma-delta T cells. This crucial difference between mouse and human gamma-delta T cells compels us to examine directly in an in vivo model of human neoplasia the behavior of human gamma T cells, and to explore receptor-ligand interactions between Vgamma2Vdelta T cells and lymphoid, myeloid, or epithelial tumor cells. We will identify which of these receptor-ligand interactions is important in human gamma-delta T cell-mediated antineoplastic activity in an in vivo SCID mouse model. We will attempt to activate, with specific antigens, human VgammaVdelta2 T cells transplanted into SCID mice to test the hypothesis that such activation will boost gamma-delta T cell-mediated antineoplastic effects. Finally, we will attempt to modulate gamma-delta T cell function in healthy humans by ingestion of antigens recognized by gamma/delta T cells. These studies will thus help define the role of VgammaVdelta2 T cells in human tumor immunity.